Benzoxazinediones

ABSTRACT

Novel benzoxazinediones of the formula:   WHEREIN R1 is hydrogen or methyl and R2 is hydrogen, alkyl of from one to four carbon atoms, or aralkyl of from seven to 11 carbon atoms; and to a method of controlling sea lamprey.

United States Patent 1 Fuchsman I54] BENZOXAZINEDIONES [75] Inventor: Charles H. Fuchsman, Cleveland Heights, Ohio [73] Assignee: Ferro Corporation, Cleveland, Ohio [22] Filed: Feb. 24, 1971 [21] '-Appl. No.: 118,544

UNITED STATES PATENTS 3,355,453 [1/1967 Hasspacher 260/244 OTHER PUBLICATIONS Veibel et al., Chem. Zentralblatt, (1944) p. I73.

{451 Mar. 27, 1973 Primary ExaminerHarry I Mozitz Att0rneyMilton L. Simmons ABSTRACT Novel benzoxazinediones of the formula:

wherein R is hydrogen or methyl and R is hydrogen alkyl of from one to four carbon atoms, or aralkyl of from seven to II carbon atoms; and to a method of controlling sea lamprey.

4 Claims, No Drawings BENZOXAZINEDIONES BACKGROUND OF THE INVENTION In recent years the lamprey has become a serious threat to the extermination of game fish particularly in the Great Lakes of North America. Several compounds have been suggested for use in controlling lamprey but most of these compounds destroy the game fish at a concentration very close to that which becomes lethal to lamprey larvae. Thus with these compounds it is necessary to destroy the game fish with the lamprey and then restock the stream with more game fish.

DESCRIPTION OF THE INVENTION It is now been discovered that a new class of benzoxazinediones can be employed to control lamprey some of which compounds are selective to lamprey without harming desirable game fish such as rainbow trout.

The novel compounds of the invention can be represented by the formula:

wherein R is hydrogen or methyl and R is hydrogen, alkyl of from one to four carbon atoms, or aralkyl of from seven to 11 carbon atoms. Exemplary of suitable alkyl are methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tertiarybutyl. Exemplary of suitable aralkyl are benzyl, alpha-methylbenzyl, para-methylbenzyl, and paratert.-butylbenzyl. The nitro group can be in any substituent position on the phenyl ring, but preferably in positions meta or para to the point of attachment to the nitrogen atom.

Represent examples of compounds of the invention are:

8-tert.-butyl-6-chloro-3-(4-nitrophenyl)-2H-l ,3-

benzoxazine-2,4-(3H)-dione 8-benzyl-6-chloro-3-( 4-nitrophenyl )-2H-l ,3-benzoxazine-2,4-(3H)-dione 6-chloro-3-(4-nitrophenyl)-2H- l ,3-benzoxazine-2,4-

(3H)-dione 8-tert.-butyl-6-chloro-5-methyl-3-(4-nitrophenyl)- 2H-l,3-benzoxazine-2,4-(3H)-dione 6-chloro-5-methyl-3-(4-nitrophenyl)-2H-1,3-

benzoxazine-2,4-(3H)-dione 8-tert.-butyl-6-chloro-3-( 3-nitrophenyl)-2H-l ,3-

benzoxazine-2,4-(3H)dione 6-chloro-3-(2-nitrophenyl)-2H- l ,3-benzoxazine-2,4-

(3H)-dione 8-alpha-methylbenzyl-o-chloro-3-(4-nitrophenyl)- 2H-l ,3-benzoxazine-2,4-( 3H )-dione 8-p-tert.-butylbenzyl-6-chloro-3-(4-nitrophenyl)- 2H-1,3-benzoxazine-2,4-(3H)-dione The utility of the compounds of the invention as lamprecides and the selectivity of certain compounds with respect to larval lampreys over rainbow trout, are illustrated by the following examples. The tests were carried out in lO-liter glass battery jars (IO-inch diameter), each containing 6 liters of solution. The jars were aerated by means of standard stone airbreakers to maintain oxygen levels at near-saturation. Temperatures (55 F.) were held constant by immersion of the testjars in a water bath.

Test animals were larvae of the sea lamprey (Petromyzon marinus) and fingerling rainbow trout (Salmo gairdneri), both ranging from about 3.0 to about 5.0 inches in length. After the animals were tempered and acclimated to the test temperature, appropriate amounts of halo-nitrosalicylanilide, in acetone as intermediate solvent, were added to produce the desired concentrations. Other conditions and results are given in the following tables.

TABLE I 8-tert.-butyl-6-chloro-3-(4-nitrophenyl)-2H-l ,3- benzoxazine-2,4-(3H)-dione.

[Water Source: Lake Huron.

Test Period: 24 hours' Water Temperature: 55 F. ]v

Larval lampreys Rainbow trout Concentration Num-Num- Morin parts/' her her tality Number Mortality million of of of of test (percentage tests test total animals of total anitest test animals) mals animals) 0.01 l 2 0.0 2 0.0 0.05 l 2 100.0 2 0.0 0.07 l 2 100.0 2 0.0 0.09 l 2 100.0 2 0.0 0.1 l 2 100.0 2 0.0 0.3 l 2 100.0 2 l00.0

TABLE II 6-chloro-3-(4-nitrophenyl)-2H-l ,3-benzoxazine-2,4-

(3H )-dione [Water Source: Lake Huron.

Test Period: 24 Hours.

Water Temperature: 5 5 F.]

Larval lampreys Rainbow trout Concen- Numtration ber Num- Morin parts] of her tality Number Mortality million tests of of of test (percentage tests test total animals of total ani test anitest animals) mals) mals) 0.07 l 2 0.0 2 0.0 0.09 l 2 100.0 2 0.0 0.1 I 2 100.0 2 0.0 0.3 l 2 l00.0 2 50.0 0.5 l 2 I00.0 2 [00.0

TABLE III 8-benzyl-6-chIoro-3-(4-nitrophenyl)-2H-l ,3- benzoxazine-2,4-(3H )-dione [Water Source: Lake Huron.

Test Period: 24 Hours.

Water Temperature: 5 5 F.]

Larval lampreys Rainbow trout Concen- Numtration ber Num- Morin parts/ of her tality Number Mortality million tests of of of test (percentage test total animals of total anitest anitest animals) mals mals 0.1 l 2 0.0 2 0.0 0.3 l 2 100.0 2 50.0 0.5 1 2 100.0 2 100.0

It is apparent from the above data that the compounds of Tables 1, 11 and Ill and particularly 1 and 11, are selective toxicants to lamprey larva and for this reason are the preferred compounds of the invention.

The compound 6-chloro-3-(4-nitrophenyl)-2H-1,3- benzoxazine-2,4-(3H)-dione is also an effective bacteriostat and it inhibits the growth of Staphylococcus aureus at 2ppm in nutrient agar. To test for effect on bacteria the compounds are incorporated in nutrient agar to various dilutions. The plates are inoculated with bacteria and are incubated at 37 C. for 48 hours then observed for evidence of bacterial growth.

The novel compounds of the invention can be prepared by reacting the appropriate nitrosalicylanilide or its alkali metal salt with an alkyl chloroformate ester preferably in the presence of a solvent, which lacks free hydroxyl groups. The reaction can be conducted at a temperature between about C. and about 120 C. in between about 1% and about 4 hours.

Exemplary of suitable chloroformate asters are ethyl chloroformate, methyl chloroformate, isopropyl chloroformate and phenyl chloroformate.

Exemplary of suitable solvents are the aliphatic compounds such as heptane, heterocyclic compounds such as pyridine, amides such as N,N-dimethylformamide and aromatic compounds such as benzene and toluene. The amides may also serve to catalyze the reaction.

The substituted nitrosalicylanilides can be prepared by treating the appropriate salicylic acid with a nitroaniline preferably in the presence of a solvent and a dehydrating agent and catalyst. Exemplary of suitable solvents are alkanes such as heptane, aromatic compounds such as benzene, toluene and chlorobenzene. Exemplary of suitable dehydrating agents are thionyl chloride and phosphorous trichloride. Exemplary of suitable catalysts are the N,N-dimethy1amides such as dimethylformamide, dimethylacetamide and dimethylpropionamide. The reaction can be conducted at a temperature between about 80 and about 150 C. in a period between about 1 and about 12 hours at atmospheric pressure.

The following examples will serve to illustrate the invention. All percentages are by weight.

EXAMPLE 1 8-t-butyl-6-chloro-3 4-nitrophenyl)-2l-l-l ,3- benzoxazine-2,4-(3H)-dione To a 200 ml. reaction flask equipped with a stirrer, thermometer, dropping funnel and reflux condenser with drying tube were charged 30 ml. of pyridine and 10.0 grams of 3-tert.-butyl-5-chloro-4'-nitrosalicylanilide (0.029 mole). Ethyl chloroformate (3.1 grams, 0.029 mole) was added dropwise to the solution in onehalf hour at 25-30 C. The reaction mixture was stirred at 25 C. for 1 hour and then at 110 C. for 2 hours. After cooling to 25 C. the mixture was poured into 300 ml. of ice water. The precipitate was filtered,

washed with water and recrystallized from methanol to produce 2.6 grams (24.2 percent) of the subject product; m.p. l834 C.

EXAMPLE 2 In accordance with the procedure of Example l, 6- ch1oro-3-(4-nitropheny1)-2H-l ,3-benzoxazine-2,4- (3H)-dione was produced in 12.5 percent yield from an equivalent quantity of 5-chloro-4'-nitrosalicylanilide; (m.p. 299 300c.

EXAMPLE 3 8-benzyl-6-chloro-3-(4-nitrophenyl)-l ,3-(2H)- benzoxazine-2 ,4-( 3H )-dione A mixture of 38.2 grams of 3-benzyl-5-chloro-4- nitrosalicylanilide (0.1 mole), 5.4 grams of NaOCH (0.1 mole) and 100 ml. of dimethylformamide was heated to boiling and 10 ml. of distillate was collected. After cooling to 25 C., 10.8 grams of ethyl chloroformate (0.1 mole) was added dropwise during a h-hour period. The solution was then stirred at reflux for 3 hours, cooled to 25 C. and poured into 600 ml. of water. The solids were collected on a Buchner funnel, washed with water and dried. After recrystallization from a heptane-toluene mixture, the subject product, 19.8 grams (48.5 percent) of crystals was recovered; m.p. l4l-4C.

EXAMPLE 4 In accordance with the procedure of Example 3, 8- tert.-butyl-6-chloro-5-methyl-3-(4-nitrophenyl)-2H- l,3-benzoxazine-2,4-(3H)-dione was prepared from 3- tert.-butyl-5-chloro-6-methyl-4-nitrosalicylanilide and ethyl chloroformate in 25.7 percent yield; m.p. l43-6 C.

EXAMPLE 5 Preparation of 3-tert.-butyl-5-chloro-4- nitrosalicylanilide To a 500 ml. reaction flask fitted with a stirrer, thermometer and condenser topped with a drying tube was charged 45.6 grams (0.2 mole) of 3-tert.-butyl-5- chlorosalicylic acid, 200 ml. of heptane and 26.3 grams of thionyl chloride (0.223 mole), and 5 ml. of dimethylformamide. The mixture was slowly warmed to C.

EXAMPLE 6 Preparation of 3-tert.-butyl5-chloro- 6-methyl-4'- nitrosalicylanilide In a 500 ml. reaction flask equipped with a stirrer, thermometer and condenser topped with a drying tube was charged 48.5 grams of 3-tert.-butyl-5-chloro-6- EXAMPLE 7 Preparation of 3-benzyl-5-chloro-4-nitrosalicylanilide In accordance with the procedure of Example 6 the subject compound was prepared having a m.p. l868 The concentration of toxicant will vary considerably upon conditions such as temperature, pH of the water, types of food and game fish, and the like and is best determined experimentally by laboratory tests stimulating conditions of actual proposed use. To employ the toxicant, the lamprecidal composition can be added directly to the water in the form of a fine powder, with or without wetting or conditioning agents or the compound can be added in liquid form as solutions, suspensions or emulsions. These procedures are more fully discussed in US. Pat. No. 2,821,499 which is herein incorporated by reference. Accordingly the process of the invention is broadly a process for controlling lamprey comprising treating said lamprey with a waterdispersible composition said composition comprising a minor but effective amount of toxicant compound of the invention.

I claim:

1. 8-tert.-butyl-6-chloro-3-(4-nitrophenyl )-2H-1 ,3- benzoxazine-2,4-( 3H)-dione.

2. 6-chloro-3-(4-nitrophenyl)-2H-l ,3-benzoxazine- 2,4-(3H)-dione.

3. 8-benzyl-6-chloro-3-(4-nitrophenyl)-2H-l ,3- benzoxazine-2,4-( 3H)-dione.

4. 8-tert.-butyl-6-chloro-5-methyl-3-(4-nitrophenyl)- 2H 1 ,3-benzoxazine-2,4-( 3H)-dione. 

2. 6-chloro-3-(4-nitrophenyl)-2H-1,3-benzoxazine-2,4-(3H)-dione.
 3. 8-benzyl-6-chloro-3-(4-nitrophenyl)-2H-1,3-benzoxazine-2,4-(3H)-dione.
 4. 8-tert.-butyl-6-chloro-5-methyl-3-(4-nitrophenyl)-2H-1,3-benzoxazine-2,4 -(3H)-dione. 